# Neutrophil elastase in obesity-related fatty liver diseases

> **NIH NIH R01** · BOSTON UNIVERSITY MEDICAL CAMPUS · 2020 · $419,252

## Abstract

Summary
Obesity is the primary factor that contributes to the development of nonalcoholic fatty
liver diseases (NAFLD), including steatosis and nonalcoholic steatohepatitis (NASH),
and fibrosis in the liver. However, the molecular and cellular events that initiate and
propagate obesity-related steatosis, inflammatory damage, and fibrotic remodeling in the
liver remain unclear. We observed that a fat- and fructose-enriched diet increases pro-
inflammatory neutrophil production preceding leukocyte infiltration, lipid deposition, and
inflammatory damage in the liver. However, neutrophil elastase (NE) knockout (KO)
mice or mice treated with an NE inhibitor are resistant to obesogenic diet-induced
inflammation, lipid deposition, and fibrosis in the liver. Based on our preliminary data, we
hypothesize that inhibition of NE prevents obesity-induced proinflammatory neutrophil
production via altering NAD-dependent deacetylase Sirtuin 1 (Sirt1) signaling pathway in
neutrophils. Deletion of NE also activates AMP-kinase (AMPK), increases the
expression of peroxisome proliferator-activated receptor alpha (PPARα), and enhances
mitochondrial gene expression and fatty acid oxidation, attenuating obesogenic diet-
induced steatosis in the liver. Furthermore, inhibition or deletion of NE mitigates
obesogenic diet-induced accumulation of inflammatory macrophages and T-helper 17
cells, inflammatory damage, and collagen deposition in the liver. In this proposal, we will
evaluate if Sirt1 in neutrophils, and if PPARα and AMPKα in the liver are required for the
beneficial effects of NE inhibition on diet-induced NASH. To understand how NE
inhibition regulates diet-induced liver fibrotic remodeling, we will also explore the
molecular basis by which neutrophils interact with other immune and non-immune cells
in the liver. Successful completion of this project will shed new light on molecular and
cellular mechanisms by which inhibition of NE as a potential therapeutic approach for
obesity-related fatty liver diseases.

## Key facts

- **NIH application ID:** 10099752
- **Project number:** 1R01DK126949-01
- **Recipient organization:** BOSTON UNIVERSITY MEDICAL CAMPUS
- **Principal Investigator:** Zhen Yue Jiang
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $419,252
- **Award type:** 1
- **Project period:** 2020-09-15 → 2023-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10099752

## Citation

> US National Institutes of Health, RePORTER application 10099752, Neutrophil elastase in obesity-related fatty liver diseases (1R01DK126949-01). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10099752. Licensed CC0.

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